tbuckley/cabot-search huggingface dataset:
Building a predictive model for outcomes with [<sup>177</sup>Lu]Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer using VISION data: Preliminary results.
Authors: Ken Herrmann, Andrei Gafita, Johann S. De Bono, A. Oliver Sartor, Kim N. Chi, Bernd J. Krause, Kambiz Rahbar, Scott T. Tagawa, Johannes Czernin, Ghassan El-Haddad, Connie Wong, Zhaojie Zhang, Celine Wilke, Osvaldo Mirante, Michael J. Morris, Karim Fizazi
Journal: Journal of Clinical Oncology (2023)

5028 Background: 177 Lu-PSMA-617 is approved in adults with PSMA+ metastatic castration-resistant prostate cancer (mCRPC). This analysis of VISION data sought to build predictive models for clinical outcomes after 177 Lu-PSMA-617. Methods: In VISION, adults with PSMA+ mCRPC received 177 Lu-PSMA-617 (7.4 GBq every 6 weeks, ≤6 cycles) plus protocol-permitted standard of care (SoC) or SoC alone. In this post hoc analysis, 29 baseline parameters were assessed for prognostic and predictive value on overall survival (OS), radiographic progression-free survival (rPFS) and PSA response (≥50% reduction; PSA50). Parameters associated with outcome regardless of treatment were prognostic, and those associated with outcome after treatment with 177 Lu-PSMA-617+SoC vs SoC were predictive. Cox proportional hazards (OS and rPFS) or logistic regression (PSA50) models were used in univariate analyses for parameter selection and to build statistical models. Here, univariate analyses are presented. Multiplicity was corrected by use of q values (ɑ = 0.05). Results: Data from 831 adults were analyzed. In initial univariate analyses, 76%, 69% and 38% of parameters assessed were prognostic for OS, rPFS and PSA50, respectively; fewer were predictive of better outcomes after 177 Lu-PSMA-617+SoC vs SoC (subset shown). Conclusions: Baseline prognostic and predictive parameters were identified for OS, as well as for rPFS and PSA50, in adults with mCRPC in VISION receiving 177 Lu-PSMA-617+SoC or SoC alone. For clinical application, select parameters will be reassessed categorically, and multivariate predictive models will be developed using identified parameters and parameter shrinkage.[Table: see text]
Carcinoembryonic antigen (CEA) expression in human tumors: A tissue microarray study on 15,413 tumors.
Authors: Kristina Jansen, Lara Kornfeld, Maximilian Lennartz, Niclas C. Blessin, Doris Höflmeyer, Sebastian Dwertmann Rico, Simon Kind, Florian Viehweger, Christoph Fraune, Natalia Gorbokon, Claudia Hube-Magg, Anne Menz, Eike C. Burandt, Guido Sauter, Ronald Simon, Martina Kluth, Stefan Steurer, Andreas H. Marx, Sarah Minner, Christian Bernreuther
Journal: Journal of Clinical Oncology (2023)

e15181 Background: Carcinoembryonic antigen (CEA) is a cell surface glycoprotein which is overexpressed in various cancers but reported prevalence data vary considerably for many tumor types. Because of its overexpression in various cancer types and the limited expression in normal tissue CEA has become a potential drug target with several potential drug candidates currently being evaluated. CEA is also shed into the blood stream, so that CEA measurement in the serum is used as a tool for early detection and recurrence monitoring of cancer. Methods: To comprehensively determine CEA expression in normal and neoplastic tissues, a tissue microarray containing 15,413 samples from 120 different tumor types and subtypes as well as 76 different normal tissue types were analyzed by immunohistochemistry. Results: CEA was detectable in 65 (54.2%) of 120 tumor categories including 49 (40.8%) tumor types with at least one strongly positive case. CEA positivity was most common in colorectal adenomas (100%) and carcinomas (98.7%), other gastrointestinal adenocarcinomas (61.1%-80.3%), medullary carcinomas of the thyroid (96.3%), pulmonary adenocarcinoma (73.7%), mucinous carcinomas of the ovary (79.8%) and the breast (43.2%), squamous cell carcinomas of various sites (30.2%-69.1%), and small cell carcinomas of the lung (64.3%), the urinary bladder (38.9%), and the prostate (50.0%) as well as non-invasive papillary urothelial carcinoma pTa G3 (33,6%), pTa G2 high-grade (25,0%) and pTa G2 low-grade (5,7%). High CEA expression was linked to high grade tumors (p &lt; 0.0001) and invasive growth (p &lt; 0.0001) in urinary bladder cancer as well as estrogen receptor positivity (p = 0.0005) and HER2 positivity (p = 0,0158) in invasive breast cancer of no special type. In 1.250 colorectal adenocarcinomas, reduced CEA expression was associated with mismatch repair deficiency (p &lt; 0.0001) but not with pT and pN stage. CEA expression level was unrelated to clinico-pathological tumor parameters in adenocarcinomas of the pancreas and the stomach, endometroid endometrium carcinoma as well as in serous and endometroid carcinomas of the ovaries. Conclusions: In summary, CEA is abundantly expressed in a broad range of epithelial neoplasms. Our data thus identify various tumor entities where CEA positive cancers might best benefit from CEA serum monitoring and anti-CEA therapies.
Efficacy of immunotherapy in MSI metastatic colorectal cancer patients: A Real-World Italian multicentric retrospective study (Colon-MSI Study).
Authors: Francesco Iachetta, Chiara Cremolini, Francesco Caputo, Giamaica Ciardiello, Donatella Iacono, Fabio Gelsomino, Ilaria Bernardini, Marco Maria Germani, Alessandra Romagnani, Angela Damato, Marco Brugia, Margherita Ratti, Sara Santucci, Stefania Rapisardi, Francesca Di Fabio, Ingrid Garajová, Michela Frisinghelli, Carlo Aschele, Michele Palazzo, Carmine Pinto
Journal: Journal of Clinical Oncology (2023)

e15595 Background: The treatment with Immune checkpoint inhibitors (ICIs) is the gold standard therapy in metastatic colorectal cancer (mCRC) patients (pts) with microsatellite instability (MSI). The aim of the study was to describe a cohort of MSI mCRC pts treated with ICIs, before pembrolizumab approval, to evaluate efficacy and toxicity in a real-world setting and to identify possible predictive factors of response. Methods: We retrospectively collected data of pts with MSI mCRC treated with ICIs (anti-PD1 or anti-CTLA-4 antibodies, or in combination) before June 30, 2021, in 14 Italian Cancer Centers. The OS was calculated from the diagnosis of metastatic disease, and the PFS from the beginning of ICIs. Survival analyses were stratified between treatment naïve and pre-treated pts. We explored the correlation between clinicopathological factors and refractory pts who underwent progression disease (PD) within 3 months from the start of ICI. Results: In this preliminary analysis, we reported 60 consecutive pts with data available. Among all, 30 (50%) were male, 37 (62%) with ECOG PS 0-1; 21 (35%) were at stage IV, and 37 (62%) had right colon tumor site. The most common metastatic sites were lymph nodes, liver, and peritoneum, and 34 (57%) pts had a single metastatic site. 23 (38%) pts had a mucinous adenocarcinoma, and 20 (33%) were BRAF mutated. Nivolumab, Pembrolizumab, and Ipilimumab plus Nivolumab were administered in 24 (40%), 34 (57%), and 2 (3%) pts, respectively, and as first-line therapy in 13 (22%) pts. The median duration of treatment was 22 months (0-43), with 21 pts still ongoing. 13 (22%) pts were refractory to ICIs, and only 4 (7%) pts discontinued treatment for G3-G4 adverse events. The OS, PFS and DCR were different between treatment naïve and pre-treated pts with a positive trend (not statistically significant) toward untreated pts (Table 1). Male gender (p = 0.03), stage IV (p = 0.04), and ≥ 2 metastatic sites (p = 0.01) were significantly associated with refractory ICIs pts, but none of these factors was correlated with poor outcomes in multivariate analysis. Conclusions: Our preliminary data confirm that immunotherapy is an effective and well-tolerated treatment in MSI mCRC pts, with long-term clinical outcomes reported. These results suggest better outcomes when ICIs are administered in the first-line setting. Further analysis will be provided after the completion of the accrual. [Table: see text]
COVID-19 induced remission of biliary and renal cell carcinomas.
Authors: Jocelyn L Tan
Journal: Journal of Clinical Oncology (2023)

e14598 Background: Clear cell renal carcinoma and cholangiocarcinoma are resistant to standard therapy. Complete remissions are rare. SARS-CoV-2 (COVID-19) boosts anti-viral immune responses but effects on cancers are unknown. Case reports of hematologic cancer remissions after COVID infection are emerging. Anti PD1/PD-L1 antibody therapy have prolonged remission in 20% of solid tumor patients. mRNA COVID-19 vaccines and COVID-19 active infections create anti-viral immune responses - increased IgG titers, SARS-CoV-2-specific antibodies, and boost T-cell response. Anti PD-1/PD-L1 antibodies immune responses, are presumed independent of the immune response to COVID vaccination/infection. Two previous case reports of hematologic remission were seen after COVID infection. (Hodgkins, multiple myeloma). There are no cases of solid cancer remission after COVID-19 exposure. Methods: Three patients with solid cancers and complete/near complete radiographic remissions after COVID-19 exposure. Two on low carbohydrate diets. History, dietary course and clinical outcomes are presented. Results: Case 1: 58 year old male diagnosed with stage IV clear cell renal carcinoma (lung nodules, mediastinal nodes). After 5 years he progressed on Sunitinib and began Nivolumab. His cancer stabilized but hypophysitis, diarrhea, severe jaw pain ended his treatment. After COVID-19 booster vaccine, he became anorexic, lost 50 lbs over 8 weeks (267 to 211 lb). Relapse was suspected but PET CT showed complete resolution of his lung nodules and adenopathy. Asymptomatic and in remission over 9 months post vaccine. Case 2: 51 year old male heavily pretreated stage 4 renal cell cancer, bone, liver, nodal metastases. On Nivolumab with stable disease but after COVID booster vaccine had high fever, fatigue, myalgia. PET CT scans later showed near complete resolution of his bony, hepatic and nodal metastatic sites. Case 3: 75 year old male with unresectable cholangiocarcinoma on second line Atezolizumab. COVID-19 infection was followed by complete radiographic remission. Conclusions: Effects of SARS-CoV-2 (COVID-19) on cancers remain unknown. Few case reports of cancer remissions after infections are emerging. These are two cases of renal cell cancers in complete remission after COVID-19 vaccination while on immunotherapy. Both followed low glycemic diets. Third case was a complete remission of biliary cancer after an acute COVID-19 infection. Proposed anti-cancer mechanisms - pathogen specific T cell action, anti-inflammatory effects against COVID-19 infection, cross-reactivity against tumor antigens, natural killer cell activation. COVID-19 proteins have oncolytic properties - HIV related B cell apoptosis and Coxsackievirus A21 oncolytic effects on myeloma and CD138+ plasma cells via intercellular adhesion molecule interaction. COVID-19’s effects plus the anti PD-1/PD-L1 antibodies immune response may be synergistic and merits further research.
Cerebrospinal fluid immunological cytokines to predict intracranial tumor response to immunotherapy in non-small cell lung cancer patients with brain metastases: GASTO 1060.
Authors: Likun Chen, Meichen Li, Jing Chen, Hui Yu, Baishen Zhang, Xue Hou
Journal: Journal of Clinical Oncology (2023)

2040 Background: Immunotherapy has been the standard first-line therapy in patients with advanced non-small cell lung cancer (NSCLC), and shown a certain efficacy for patients with brain metastases. however, the appropriate predictive biomarkers for intracranial tumor response to immunotherapy are unclear. We conducted this prospective study to explore the immunological cytokines in cerebrospinal fluid (CSF) to predict intracranial tumor response to immunotherapy in NSCLC patients with brain metastases. Methods: We prospectively enrolled treatment-naive, EGFR/ALK wild-type NSCLC patients with brain metastases in this study. Patients received chemotherapy plus camrelizumab (a humanized anti-PD-1 monoclonal antibody) as first-line treatment, and paired plasma and cerebrospinal fluid (CSF) samples were collected at baseline and first treatment evaluation (8-week). All samples were detected for 92 Immuno-Oncology cytokines using the Olink panels, and were explored for predictive biomarkers to immunotherapy. The Mann-Whitney U test was performed to compare the immunological cytokine expression between intracranial response and non-response groups. And logistic LASSO regression model was used to variate selection and develop a CSF immuno-cytokine model to predict intracranial tumor response. Results: Between April 2020 and May 2022, a total of 28 patients were enrolled this study.At baseline, most immunological cytokines were significantly lower in paired CSF than in plasma, whereas a subset including CD83, PTN, TNFRSF21, TWEAK, ICOSLG, DCN, IL-18 and MCP-1 were increasing expressed in CSF samples. For patients with objective intracranial tumor response compared to patients with non-response, the baseline CSF levels of LAMP3 were significantly higher, whereas the CXCL10, IL-12, CXCL11, IL-18, TIE2, HGF and PDCD1 levels were significantly lower. And patients with lower HGF, IL-18 or PDCD1 levels had significantly longer intracranial progression-free survival to immunotherapy. The above CSF immunological cytokines were significantly decreased at first treatment evaluation in patients with intracranial tumor response. Our logistic CSF immuno-cytokine model selected TIE2, IL-18, LAMP3, PDCD1 and IL-12 that were significantly associated with intracranial tumor response, and yielded a mean AUC of 0.91, compared to PD-L1 expression (mean AUC of 0.72). Conclusions: Immunological cytokines in CSF could predict intracranial tumor response to immunotherapy in NSCLC patients with brain metastases, and findings require validation in a larger prospective cohort.
Subjective and objective hearing loss among US adult cancer survivors: A national cross-sectional study.
Authors: Qian Wang, Changchuan Jiang, Chi Wen, Hui Xie, Yannan Li, Yaning Zhang, Leila Jean Mady, Debora S. Bruno, Giselle Dutcher, Lauren Chiec, Afshin Dowlati, Melinda Laine Hsu
Journal: Journal of Clinical Oncology (2023)

e24059 Background: Approximately 13% of adults had some degree of hearing loss (HL), and the prevalence is higher among adults aged 65 and over (30.9%). Approximately 50-80% of the childhood, adolescent and young adult cancer survivor population report HL following treatment with high-dose platinum-based chemotherapy, head or brain radiotherapy. We aimed to 1) estimate the prevalence of subjective and objective hearing loss (HL) among cancer survivors and compare to the general population; 2) assess the performance of subjective HL questions in detecting HL by audiometry among cancer survivors. Methods: Adults aged 20-80 years old were selected from the National Health and Nutrition Examination Survey. The weighted prevalence of subjective HL (having troublesome hearing and tinnitus) and objective HL (speech-frequency HL and high-frequency HL) by audiometry test was calculated. Chi-square test and multi-adjusted logistic regression models were used to compare HL between cancer survivors and the general population. To evaluate the performance of subjective HL questions as a tool to screen for objective HL by audiometry, area under the curve (AUC) were estimated using age-and gender- adjusted logistic regression. Results: Compared to the general population, cancer survivors had a statistically significantly higher prevalence of troublesome hearing ( a OR = 1.43; 95%CI:1.22-1.68), tinnitus ( a OR = 1.28; 95%CI:1.08-1.53), speech-frequency HL (SFHL) ( a OR = 1.44; 95%CI:1.20-1.73) and high-frequency HL (HFHL) ( a OR = 1.74; 95%CI:1.45-2.09). The sensitivity and specificity of the combined subjective questions “whether having troublesome hearing and/or tinnitus” in detecting HL was shown in Table. The age- and gender- adjusted AUC for detecting SFHL and HFHL using combined questions was 0.88 and 0.90. Conclusions: Cancer survivors have a significantly higher prevalence of both subjective and objective HL, but a lack of hearing examination. Two subjective HL questions could accurately identify those have true HL and provide a simple and efficient screening tool for providers. Cancer survivors and their families should be educated and encouraged to discuss hearing concerns, and providers should facilitate raising awareness and provide early screening and timely referral when HL is identified.[Table: see text]
Antitumor activity of AX-0085, a novel AXL kinase inhibitor: Analysis of apoptotic cell death in triple-negative breast cancer cells.
Authors: Myeong Jun Choi, SangHyeon Woo, DongHa Kim, Keshav Karapurkar Janardhan, SungIl Yoon, Young Jun Park, Jaesang Kim, Jun Young Jang, Byung Woo Han, Ramakrishna Suresh, Kye-Seong Kim
Journal: Journal of Clinical Oncology (2023)

e15120 Background: Triple-negative breast cancer (TNBC) is insensitive to targeted therapies due to the negative expression of human epidermal growth factor receptor-2, estrogen receptor and progesterone receptor. TNBC cells express higher levels of AXL more often than other breast cancer subtypes. The receptor tyrosine kinase AXL plays a role in survival, invasion, migration, epithelial-mesenchymal transition (EMT), metastasis, resistance, and immune suppression in cancer cells including in TNBC. Thus, AXL is a promising therapeutic target for the treatment of TNBC, and we developed a new small-molecule AXL inhibitor, AX-0085. Methods: The interaction mechanism between AX-0085 and AXL was studied by molecular dynamic simulations, cell-based kinase assay, and western blotting in TNBC cells. We investigated the anti-tumor activity of AX-0085 on the AXL-dependent pro-tumorigenic properties such as cell proliferation, invasion, migration, EMT, and immune suppression (PD-L1 expression) in TNBC cell lines and investigated in vivo efficacy of AX-0085 with the 4T1 xenograft model. Results: In the molecular dynamic simulations, estimated binding energy of AX-0085 and cabozantinib to AXL was -10.1Kcal/mol and -8.1Kcal/mol, respectively. AX-0085 was made a hydrogen bond with catalytically important residue Lys567 and blocked the activation of AXL by inhibiting the salt bridge with Lys567-Glu585. AX-0085 (IC 50 : 4.4nM for AXL kinase in cell-based kinase assay) was one of the most potent AXL inhibitors. AX-0085 showed a high antitumor activity against all TNBC subtypes and was a more potent anti-proliferative activity than other kinase inhibitors in MDA-MB-231 cell line. AX-0085 effectively blocked the activation of AXL in TNBC and further inhibited AXL-dependent pro-tumorigenic events such as cell proliferation, invasion, migration, EMT, and PD-L1 expression in TNBC cell. AX-0085 induced cell cycle arrest at G1 phase and suppressed the expression of CDK2 and Cyclin E in TNBC. AX-0085 promoted apoptotic cell death by up-regulating cleaved caspase-9 and down-regulating Bcl-2 in TNBC. Pharmacological investigation showed that the AX-0085 treated tumors displayed a dose-dependent reduction in volume and weight of the tumors in the 4T1 mouse xenograft. Conclusions: Our results demonstrated that AX-0085 selectively blocks AXL activation which confers an effective therapeutic value in the treatment of TNBC. Currently, AX-0085 is undergoing non-clinical trials.
Biomarkers to predict the efficacy of immune checkpoint inhibitors in patients with non-small-cell lung cancer with actionable genetic alterations.
Authors: Soojin Jun, Hyun Ae Jung, Myung-Ju Ahn, JinSeok Ahn, Se-Hoon Lee, Jong Mu Sun, Sehhoon Park, Juhee Cho
Journal: Journal of Clinical Oncology (2023)

e21175 Background: Although the efficacy of immune checkpoint inhibitors (ICI) in patients with actionable genetic alterations (AGAs) in non-small-cell lung cancer (NSCLC) has been known to be modest, some patients demonstrated improved survival. Thus, this study aimed to find predictive biomarkers for ICI in patients with NSCLC with various AGAs and to identify the predictive biomarkers for ICI efficacy. Methods: We compared the progression-free survival (PFS) of 324 advanced NSCLC patients who received ICI monotherapy (as over second-line therapy) by different AGAs from January 2018 and July 2022 at the Samsung Medical Center. To identify predictive markers of ICI, we adjusted the impacts on PFS of ICI in smoking status, PD-L1 expression, TP53, KEAP, STK11 mutation status, and steroid use during ICI monotherapy. Results: The median age was 63.1 years (range, 27.8–84.8) and 53.1% of patients was male, and 46.3% of patients was an ex-/or current smoker. A total of 324 patients were included with the following AGAs: EGFR mutation (n = 149, 46.0%), ALK rearrangement, (n = 12, 3.7%), KRAS mutation (n = 72, 22.2%), HER2 mutation or amplification (n = 34, 10.5%), and MET ex14 skipping or amplification (n = 32, 9.9%), ROS1 rearrangement (n = 9, 2.8%), BRAF V600E (n = 9, 2.8%), and RET rearrangement (n = 7, 2.2%). The median PFS was 2.0 months (95% confidence interval, 1.8–2.2) in the total AGA group. The 6-month PFS rate was 25.8% (19.5–34.3) in the group with KRAS/ BRAF V600E/ MET/ HER2 and 12.8% (8.6–19.1) in the group with EGFR/ ALK/ ROS1/ RET (P &lt; 0.01). In the group with KRAS/ BRAF V600E/ MET/ HER2, KEAP, or STK11 wild-type (P = 0.03), PD-L1 (≥1%) (P &lt; 0.01) and steroid use during ICI monotherapy due to immune-related adverse events (IRAE) (P &lt; 0.01) were related to a favorable PFS of ICI; however, no statistical significance was found for TP53 mutation and smoking status for PFS of ICI. In the group with EGFR/ ALK/ ROS1/ RET, PD-L1(≥ 50%) was the only factor that was related to a favorable PFS, and not TP53 mutation status, KEAP, or STK11. Conclusions: This study showed a difference in PFS among each type of AGAs. Although there are limitations due to the small number of patients, the KRAS/ BRAF V600E/ MET/ HER2 group had a favorable PFS compared with the EGFR/ ALK/ ROS1/ RET group . KEAP/STK11/PD-L1 status and steroid use due to IRAE predicted favorable PFS of ICI in the KRAS/ BRAF V600E/ MET/ HER2 group .